Method for manufacture of sertindole

ABSTRACT

The present invention relates to a novel method for manufacture of sertindole comprising manufacturing 5-chloro-1-(4-fluorophenyl)-indole and converting it to sertindole wherein the method for manufacture of 5-chloro-1-(4-fluorophenyl)-indole comprises reacting 5-chloro-indole with a 4-fluorophenylhalide in the presence of a base, a chelating ligand and catalytic amounts of a copper salt comprising copper(I) or copper(II) and an anion which does not interfere in an unfavourable way with the reaction.

FIELD OF THE INVENTION

The present invention relates to a new method of manufacturing thecompound 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1-H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone having the INN name sertindole anda new method of manufacturing the intermediate, 5-chloro-1-(4-fluorophenyl)-indole used in the method.

BACKGROUND OF THE INVENTION

Sertindole is a well-known antipsychotic drug having the formula

The compound was disclosed in U.S. Pat. No. 4,710,500 and theantipsychotic activity thereof was described in U.S. Pat. No. 5,112,838.Sertindole is a potent centrally acting 5-HT₂ receptor antagonist invivo and has further been disclosed to be active in models indicative ofeffects in the treatment of anxiety, hypertension, drug abuse andcognitive disorders.

A number of syntheses of sertindole have been disclosed in U.S. Pat. No.4,710,500 and WO 98/51685. 5-chloro-1-(4-fluorophenyl)-indole is a keyintermediate in these syntheses. The syntheses of5-chloro-1-(4-fluorophenyl)-indole as disclosed in U.S. Pat. No.4,710,500 and WO 98/51685 require multiple steps from commerciallyavailable starting materials, are expensive, occupy production equipmentfor prolonged periods resulting in low production capacity and result inenvironmental impact and safety. The synthesis which has been favouredso far for industrial synthesis of sertindole comprises the multiplestep synthesis of 5-chloro-1-(4-fluorophenyl)-indole as disclosed in WO98/51685.

An alternative synthetic strategy for 1-aryl-indoles is the Ullmannarylation of N-unsubstituted indoles with aryl halides catalyzed bylarge amounts of copper, typically near-stoichiometric amounts or more,as disclosed in e.g. J. Med. Chem. 1992, 35 (6), 1092-1101. The Ullmannarylation has, however, hitherto been disfavoured with regards to thesynthesis of 5-chloro-1-(4-fluorophenyl)-indole due to various problemswhich to those skilled in the art are known to apply to the Ullmannarylation in general as the reactions typically result in moderateyields, around 50%, correspondingly large amounts of colouredby-products and cumbersome work-up procedures caused by the complexationof the reaction product with the copper catalyst. These complexes oftenrequire surprisingly harsh treatment to liberate the free reactionproduct, as known to those skilled in the art.

Hence, there is a desire for new methods for manufacturing of5-chloro-1-(4-fluorophenyl)-indole. Such new methods may be advantageousin that they are more cost effective, require fewer reaction steps, havereduced impact on the environment, give higher yields, result inincreased production capacity, purer crude product and easier work-upprocedures.

Recently, Klapars et al. J.Am. Chem.Soc. 2001, 123, 7727-7729, discloseda variant of the Ullmann arylation wherein copper is present incatalytic amounts together with the chelating ligandtrans-1,2-cyclohexanediamine.

SUMMARY OF THE INVENTION

It has now surprisingly been found that it is possible to manufacture5-chloro-1-(4-fluorophenyl)-indole in an efficient way giving goodyields by arylation of 5-chloro-indole with a 4-fluorophenylhalide inthe presence of catalytic amounts of a copper salt and a chelatingligand. This reaction is surprisingly selective. Illustrative of thishigh selectivity is the fact that there is virtually no by-productsformed by reaction between the 5-chloro group of one molecule of5-chloro-indole and the nitrogen of another molecule of 5-chloro-indole.This type of side reaction would be expected from the disclosure inJ.Am. Chem.Soc. 2001, 123, 7727-7729, which illustrate the reactivity ofarylchlorides in this type of reactions. It has even more surprisinglybeen found that the chelating ligand may be as simple asethylenediamine. This reaction gives 5-chloro-1-(4-fluorophenyl)-indolein high yields and purity in a cost-effective single-step synthesis fromcommercially available starting materials.

Hence, the present invention relates to a novel method for manufactureof sertindole comprising manufacturing5-chloro-1-(4-fluorophenyl)-indole and converting it to sertindolewherein the method for manufacture of 5-chloro-1-(4-fluorophenyl)-indolecomprises reacting 5-chloro-indole with a 4-fluorophenylhalide in thepresence of a base, a chelating ligand and catalytic amounts of a coppersalt comprising copper(I) or copper(II) and an anion which does notinterfere in an unfavourable way with the reaction.

Furthermore, the present invention relates to a method for manufactureof 5-chloro-1-(4-fluorophenyl)-indole comprising reacting5-chloro-indole with a 4-fluorophenylhalide in the presence of a base, achelating ligand and catalytic amounts of a copper salt comprisingcopper(I) or copper(II) and an anion which does not interfere in anunfavourable way with the reaction.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the description and the claims, the followingdefinitions apply:

The term ‘4-fluorophenylhalide’ means any compound selected from thegroup consisting of 4-fluoro-chlorobenzene, 4-fluoro-bromobenzene and4-fluoro-iodobenzene.

The term ‘catalytic amounts’ means amounts that are significantly lowerthan stoichiometric amounts such as less than 20 mol % relative to5-chloro-indole.

The term ‘chelating ligand’ means any compound comprising at least twoatoms that are able to simultaneously coordinate to the same metal atom.

The term ‘C₁₋₆-alkyl’ refers to a branched or unbranched alkyl grouphaving from one to six carbon atoms inclusive, such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, and2-methyl-1-propyl.

The term ‘C₁₋₆-alkyl carboxylic acid’ refers to C₁₋₆-alkyl groups whichare terminated by a carboxylic acid.

The term ‘aryl’ refers to a carbocyclic aromatic group, such as phenylor naphthyl, in particular phenyl.

In one aspect the present invention relates to a method for manufactureof sertindole comprising manufacturing5-chloro-1-(4-fluorophenyl)-indole and converting it to sertindolewherein the method for manufacture of 5-chloro-1-(4-fluorophenyl)-indolecomprises reacting 5-chloro-indole with a 4-fluorophenylhalide in thepresence of a base, a chelating ligand and catalytic amounts of a coppersalt comprising copper(I) or copper(II) and an anion which does notinterfere in an unfavourable way with the reaction.

In a further aspect, the present invention relates to a method formanufacture of 5-chloro-1-(4-fluorophenyl)-indole comprising reacting5-chloro-indole with a 4-fluorophenylhalide in the presence of a base, achelating ligand and catalytic amounts of a copper salt comprisingcopper(I) or copper(II) and an anion which does not interfere in anunfavourable way with the reaction.

The embodiments described hereafter applies to all aspects of theinvention.

In one embodiment of the invention, the chelating ligand is asubstituted or unsubstituted 1,10-phenanthrolin, such as anunsubstituted 1,10-phenanthrolin. In another embodiment the chelatingligand is a compound of the formula X—(CR¹R²—(CR⁵R⁶)_(n)—CR³R⁴—Y)_(m),wherein X and Y independently are selected from NR⁷R⁸ and OR⁹, R¹—R⁹independently are selected from hydrogen, C₁₋₆-alkyl, C₁₋₆-alkylcarboxylic acid and aryl or one of R¹ and R² together with one of R⁵ andR⁶ are C₃₋₆-alkylene, m is 1 or 2, and n is 0, 1, 2 or 3. In a preferredembodiment, at least one of X and Y is NR⁷R⁸, and more preferred both ofX and Y are NR⁷R⁸. In another preferred embodiment, R⁷ and R⁸ areindependently selected from hydrogen, C₁₋₆-alkyl and C₁₋₆-alkylcarboxylic acid, and more preferred R⁷ and R⁸ are hydrogen. In yetanother preferred embodiment, R⁵ and R⁶ are hydrogen. In yet anotherpreferred embodiment, m is 1. In yet another preferred embodiment, n is0. In yet another preferred embodiment R¹—R⁴ are hydrogen, or R¹ and R³together are C₃₋₄-alkylene and R² and R⁴ are hydrogen. Preferredchelating ligands are those selected from the group comprising1,2-cyclohexanediamine, N,N,N,N-tetramethyl ethylenediamine, N,N-diethylethylenediamine, ethylenediamine, ethylenediamine N,N,N,N-tetraaceticacid (EDTA), diethylenetriamine N,N,N,N,N-pentaacetic acid (DTPA) andsubstituted or unsubstituted 1,10-phenantroline; more preferredchelating ligands are those selected from the group comprising1,2-cyclohexanediamine, N,N,N,N-tetramethyl ethylenediamine, N,N-diethylethylenediamine and ethylenediamine, and the most preferred chelatingligand is ethylenediamine.

In a preferred embodiment of the invention, the 4-fluorophenylhalide is4-fluoro-bromobenzene or 4-fluoro-iodobenzene as the reactivity of the4-fluorophenylhalides increases in the order chloro-<bromo-<iodo forthis type of reactions. In a preferred embodiment of the invention the4-fluorophenylhalide is added in a molar surplus relative to5-chloro-indole. Preferably the molar ratio4-fluorophenylhalide:5-chloro-indole is in the range from about 1.1 toabout 3, more preferred from about 1.2 to about 2.5, and most preferredfrom about 1.3 to about 2.0.

The methods of manufacture according to the present invention areadvantageous as compared to classical Ullmann arylation as they onlyrequire catalytic amounts of a copper salt, i.e. less than 20 mol %relative to 5-chloro-indole. Preferably the amount of copper salt isless than 10 mol % relative to 5-chloro-indole and even more preferredin the range from about 1 to about 5 mol %. The products made accordingto the present invention may be isolated without the harsh treatment,such as boiling in hydrochloric acid or treatment with cyanides, whichoften is necessary in order to break the complexes between copper andthe product of the classical Ullmann reactions.

Any copper salt comprising copper(I) or copper(II) and an anion whichdoes not interfere in an unfavourable way with the reaction may beapplied. Exemplary of anions, which may interfere in an unfavourable waywith the reaction, are cynaide, sulphide and selenide. Cyanide may reactas a nucleophile and compete with the indole for reaction with the4-fluorophenylhalide, whereas sulphide and selenide may inactivate thecopper catalyst. Those skilled in the art will be aware that otheranions also may interfere in an unfavourable way with the reaction andeasily realise if an anion interferes in an unfavourable way with thereaction. Preferred copper salts for use in the present invention areselected from the group comprising CuCl, CuBr, CuI, CuCl₂, CuBr₂, CuI₂,CuOCOCH₃, Cu(OCOCH₃)₂, anhydrous or hydrated CuSO₄, CuCO₃, Cu₂O andmixtures of said copper salts; more preferred copper salts are thoseselected from the group comprising CuCl, CuBr, CuI, CuCl₂, CuBr₂ andCuI₂. These work well as catalysts in the reaction and are readilyavailable to reasonable prices. The copper salt may be added in oneportion at the start of the reaction or in two or more portionsdistributed over the reaction time.

Various bases may be employed in the methods of manufacture of thepresent invention. Exemplary bases are the carbonates, hydrogencarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates,oxides and hydroxides of alkali metals. Preferred bases are potassiumand sodium carbonates as these are readily available to a low price andeasy to handle. The base is typically present in a molar excess relativeto 5-chloro-indole, preferably the amount of base is in the range fromabout 1.05 molar equivalents to about 2.5 molar equivalents.

The methods of manufacture of the present invention may be performed byheating a neat mixture of the reactants without any solvent or in asuitable solvent system. Exemplary of such solvent systems are toluene,mixtures of toluene and water, ethers such as dioxane, tetrahydrofurane(THE), diethyl ether, dimethyl ether, monoethylene glycol dimethyl ether(monoglyme) and diethylene glycol dimethyl ether (diglyme), amides suchas dimethylformamide (DMF), dimethylacetamide (DMA),N-methyl-pyrrolidone (NMP). Preferred solvents are DMF and toluene andmost preferred is DMF.

Typically the methods of manufacture of the present invention areperformed at temperatures above 80° C., preferably in the range from 90°C. to 200° C., more preferred in the range from 100° C. to 160° C.Higher yields may be obtained by pretreating the reaction system at atemperature in the range from about 30° C. to about 70° C., preferablyin the range from about 40° C. to about 60° C., for a period of timeranging from about 0.5 hour to about 20 hours, preferably in the rangefrom about 1 hour to about 15 hours, before completing the reaction at ahigher temperature as specified above. Evidently, if the solvent systemused is incompatible with the reaction temperature, such as temperaturesabove 80° C., then the method may be carried out under pressure.

EXAMPLES

The following examples is meant to illustrate various embodiments of theinvention and should not be read as limiting the scope of protection.

Chromatographic Procedures

HPLC and GC analyses were performed according to the proceduresdescribed below.

Analytical Method HPLC—5-Chloroindole Instrument HPLC HP 1100 BinaryPump Agilent 1100 Series Agilent Detector UV Agilent 1100 Series ColumnThermostat Agilent 1100 Series Autosampler Agilent 1100 SeriesIntegration Agilent Chemstation Detector UV 230 nm Column HP LichrospherC8 250 × 4 mm, 5 μm Column Temperature 40° C. Mobile Phase AWater/Acetonitrile 65:35 Mobile Phase B Water/Acetonitrile 15:85 Flow1.0 mL/min Volume injected   5 μl Run time  45 min Gradient Time % A % B 0 100  0 30  0 100 40  0 100 conditioning Runtime  40 minAssay Against External StandardSample Preparation

Weigh accurately about 50 mg of sample in a 50 mL volumetric flask andadd acetonitrile to volume. Transfer 10 mL of obtained solution in a 25volumetric flask and add acetonitrile to volume. Final concentration 0.2mg/mL.

Standard Preparation

Weigh accurately about 50 mg of Reference Standard in a 50 mL volumetricflask and add acetonitrile to volume. Transfer 10 mL of obtainedsolution in a 25 volumetric flask and add acetonitrile to volume. Finalconcentration 0.2 mg/mL

Analytical Procedure

Inject the Standard three times (at least), integrate the obtainedchromatograms and calculate Medium Area. If the Standard Deviation % isless than 1.0% inject the Sample and integrate the chromatogram.Calculate the product assay with the formula:Assay %=(Sample Area×Conc. Std×100)/(Standard Area×Sample Conc.)Where:

-   -   Sample Area=Area obtained by sample injection    -   Standard Area=Average of areas obtained by Standard injection    -   Sample Conc.=Concentration (mg/ml) of Sample    -   Standard Conc.=Concentration (mg/ml) of Standard        Analytical Method HPLC—5-chloro-1-(4-fluorophenyl)-indole

Instrument configuration as above except for the gradient. Mobile PhaseA Water/Acetonitrile 65:35 Mobile Phase B Water/Acetonitrile 15:85 Runtime 45 min Gradient Time % A % A  0 60  40 30  0 100 40  0 100conditioning Runtime 40 minAssay Against External StandardSample Preparation

Weigh accurately about 50 mg of sample in a 50 mL volumetric flask andadd acetonitrile to volume. Transfer 10 mL of obtained solution in a 25volumetric flask and add acetonitrile to volume. Final concentration 0.2mg/mL.

Standard Preparation

Weigh accurately about 50 mg of Reference Standard in a 50 mL volumetricflask and add acetonitrile to volume. Transfer 10 mL of obtainedsolution in a 25 volumetric flask and add acetonitrile to volume. Finalconcentration 0.2 mg/mL.

Analytical Procedure

Inject the Standard three times (at least), integrate the obtainedchromatograms and calculate Medium Area. If the Standard Deviation % isless than 1.0% inject the Sample and integrate the chromatogram.Calculate the product assay with the formula:Assay %=(Sample Area×Conc. Std×100)/(Standard Area×Sample Conc.)Where:

-   -   Sample Area=Area obtained by sample injection    -   Standard Area=Average of areas obtained by Standard injection    -   Sample Conc. Concentration (mg/ml) of Sample    -   Standard Conc.=Concentration (mg/ml) of Standard

Analytical Method GC—5-chloroindole and5-chloro-1-(4-fluorophenyl)-indole Instrument GC Gc Top 8000 CEInstruments Detector FID Column Zebron (ZB-1)   30 m × 0.25 mm 0.25 μmCarrier Flow (He)  1.5 mL/min Split Flow   50 mL/ml H₂ Flow   30 mL/minAir Flow  300 mL/min Volume injected   1 μL Run time   25 min Step Temp(° C.) Duration 1 120° C.  3 min 1→2 120°→220° C.  5 min 2 220° C. 20min ΔT 20° C./min T inj 220° C. T det 250° C.Assay Against External StandardInternal Standard Solution

Dilute about 2 ml of Undecane (GC Standards) with Acetone in a 250 mLvolumetric flask.

-   -   Sample Preparation

Weigh accurately about 250 mg of sample (5-chloroindole or5-chloro-1-(4-fluorophenyl)-indole) in a 25 mL volumetric flask and addInternal Standard Solution to volume. Final concentration 25 mg/mL.

Standard Preparation

Weigh accurately about 250 mg of Reference Standard (5-chloroindole or5-chloro-1-(4-fluorophenyl)-indole) in a 25 mL volumetric flask and addInternal Standard Solution to volume. Final concentration 25 mg/mL.

Analytical Procedure

Inject the Standard three times (at least), integrate the obtainedchromatograms and calculate the ratio between Area of analyte and Areaof Internal Standard. If the ratio Standard Deviation % is less than1.0% inject the Sample and integrate the chromatogram and calculate theratio as described above. Calculate the product assay with the formula:Assay %=(Sample Area Ratio×Conc. Std×100)/(Standard Area Ratio×SampleConc.)Where:

-   -   Sample Area Ratio=Area Ratio obtained by sample injection    -   Standard Area Ratio=Average of area ratios obtained by Standard        injection    -   Sample Conc.=Concentration (mg/ml) of Sample    -   Standard Conc.=Concentration (mg/ml) of Standard        Analytical Method        GC—5-chloro-1-(4-fluorophenyl)-indole—Conversion        In-Process-Control

Instrument configuration as above.

Conversion In-Process-Control

Sample Preparation

Stop the stirring and sample 0.1 mL of reaction solution. Dilute with 5ml of toluene. Filter the solution obtained and inject.

Calculate the conversion with the formula:Conversion %=(5-chloro-1-(4fluorophenyl)-indoleArea×100)/(5-Chloroindole Area+5-chloro-1-(4-fluorophenyl)-indole Area)Where:5-chloro-1-(4fluorophenyl)-indole Area=Area detected for5-chloro-1-(4-fluorophenyl)-indole5-Chloroindole Area=Area detected for 5-ChloroindoleIdentification of Product

NMR spectra were determined on a Bruker Avance 300 spectrometer

¹H-NMR CDCl₃ 300MHz (δ ppm, J HZ): 7.70 (1H, d, J=2.0); 7.49-7.39 (3H,m); 7.32 (1H, d, J=3.2); 7.30-7.17 (3H, m); 6.66 (1H, d, J=3.2).

¹³C-NMR CDCl₃ 75 MHz (δ ppm, J_(C,F) Hz): 161.68 (d, J_(C,F)=245.0);135.87 (d, J_(C,F)=2.0); 134.96; 130.62; 129.75; 126.59 (d,J_(C,F)=8.3); 126.49; 123.18; 120.97; 117.04 (d, J_(C,F)=22.0); 111.71;103.59.

¹⁹F-NMR CDCl₃ 282MHz (δ ppm): 114.94 (m).

These data are in agreement with the structure of5-chloro-1-(4-fluorophenyl)-indole.

Synthetic Examples with Toluene as Solvent

Example 1 N,N,N,N-tetramethyl ethylenediamine as ligand

A jacketed glass reactor was charged with 40 g of crude 5-chloro-indole(80% pure as determined by HPLC) (32 g, 0.211 mol), K₂CO₃ (40.2 g,0.2902 mol), 4-fluoro-bromobenzene (92.3 g, 0.5277 mol), CuI (2.5 g,1.32.*10⁻² mol), N,N,N,N-tetramethyl ethylenediamine (3.2 g, 5.28*10⁻²mol) and 80 mL of toluene. The mixture was heated to reflux (about 115°C.), under vigorous stirring, and maintained for 40 hours.

After cooling to 60° C., 80 mL of Toluene and 80 mL of water were addedand the mixture was maintained under stirring at 50° C. for ½ hour andthe organic layer was separated and treated with 80 mL of water. Theresidual carbonates were then dissolved by slow addition of aqueous HCl32% until solution reached pH=2-3. The mixture was maintained understirring at 50° C. for ½ hour the aqueous layers were eliminated. Theorganic layer was then concentrated, by solvent distillation at reducedpressure, and the crude product was obtained as an oil (47.2 g). Theyield, based on HPLC (assay against ext. Std.), was about 42%.

Example 2 N,N-diethyl ethylenediamine as ligand

Following the procedure of example 1 except that N,N-diethylethylenediamine was used in stead of N,N,N,N-tetramethyl ethylenediaminethe crude product was obtained as an oil (84 g). The yield, based onHPLC (assay against ext. Std.), was about 50%.

Example 3 Trans-1,2-cyclohexanediamine as ligand

A jacketed glass reactor was charged with 10 g of crude 5-chloro-indole(80% pure as determined by HPLC) (8 g, 5.2*10⁻² mol), K₂CO₃ (12.7 g,9.2*10⁻² mol), 4-fluoro-bromobenzene (12.7 g, 7.3*10⁻² mol), CuI (1.26g, 6.6*10⁻³ mol), trans-1,2-cyclohexanediamine (1.13 g, 9.9*10⁻³ mol)and 20 mL of toluene. The mixture was heated to reflux (about 115° C.),under vigorous stirring, and maintained for 12 hours. The conversionchecked by GC was about 79%.

After cooling to 60° C., the solid residual were filtered off and theorganic solution was then concentrated, by solvent distillation atreduced pressure, and the crude product was obtained as an oil (15.4 g)

Example 4 K₃PO₄ as base

A jacketed glass reactor was charged with 20 g of crude 5-chloro-indole(80% pure as determined by HPLC) (16 g, 0.106 mol), K₃PO₄ (18.6 g, 0.088mol), 4-fluoro-bromobenzene (46.2 g, 0.263 mol), CuI (1.25 g, 1.32*10⁻²mol), ethylenediamine (1.58 g, 2.62*10⁻² mol) 40 mL of toluene. Themixture was heated to reflux (about 115° C.), under vigorous stirring,and maintained for 22 hours. An additional amount of K₃PO₄ (9.3 g,4.4*10⁻² mol) was added and the mixture was stirred for 19 h. Theconversion checked by GC was about 42%.

After cooling to 60° C., 80 mL of Toluene and 80 mL of water were addedand the mixture was maintained under stirring at 50° C. for ½ hour andthe organic layer were separated and treated with 80 mL of water. Theresidual phosphates were then dissolved by slow addition of aqueous HCl32% until solution reached pH=2-3. The mixture was maintained understirring at 50° C. for ½ hour the aqueous layers were eliminated. Theorganic layer was then concentrated, by solvent distillation at reducedpressure, and the crude product was obtained as an oil (62.3 g).

Example 5 CuBr as catalyst source

A jacketed glass reactor was charged with 40 g of crude 5-chloro-indole(80% pure as determined by HPLC) (32 g, 0.211 mol), K₂CO₃ (40.2 g,0.2902 mol), 4-fluoro-bromobenzene (92.3 g, 0.5277 mol), CuBr (1.89 g,1.32*10⁻² mol), ethylenediamine (3.2 g, 5.28*10⁻² mol) and 80 ml oftoluene. The mixture was heated to reflux (about 115° C.), undervigorous stirring, and maintained for 32 hours. The conversion checkedby GC was about 92%.

After cooling to 60° C., 80 mL of toluene and 80 mL of water were addedand the mixture was maintained under stirring at 50° C. for ½ hour andthe organic layer was separated and treated with 80 mL of water. Theresidual carbonates were then dissolved by slow addition of aqueous HCl32% until solution reached pH=2-3. The mixture was maintained understirring at 50° C. for ½ hour the aqueous layers were eliminated. Theorganic layer was then concentrated, by solvent distillation at reducedpressure, and the crude product was obtained as an oil (64.4 g).

Example 6 CuCl as catalyst source

A jacketed glass reactor was charged with 40 g of crude 5-chloro-indole(80% pure as determined by BPLC) (32 g, 0.211 mol), K₂CO₃ (40.2 g,0.2902 mol), 4fluoro-bromobenzene (92.3 g, 0.5277 mol), CuCl (1.31 g,1.32*10⁻² mol), ethylenediamine (3.2 g, 5.28*10⁻² mol, 25%) and 80 mL oftoluene. The mixture was heated to reflux (about 115° C.), undervigorous stirring, and maintained for 32 hours. The conversion checkedby GC was about 92%.

After cooling to 60° C., 80 mL of toluene and 80 mL of water were addedand the mixture was maintained under stirring at 50° C. for ½ hour andthe organic layer was separated and treated with 80 mL of water. Theresidual carbonates were then dissolved by slow addition of aqueous HCl32% until solution reached pH=2-3.The mixture was maintained understirring at 50° C. for ½ hour the aqueous layers were eliminated. Theorganic layer was then concentrated, by solvent distillation at reducedpressure, and the crude product was obtained as an oil (7.81 g).

Example 7 CuBr₂ as catalyst source

A glass jacketed reactor was charged with 20 g of crude 5-chloro-indole(80% pure as determined by HPLC) (16 g, 0.106 mol), K₂CO₃ (20 g, 0.144mol), 4-fluoro-bromobenzene (46.1 g, 0.26 mol), CuBr₂ (1.46 g, 6.6*10⁻³mol), ethylenediamine (1.58 g, 2.6*10⁻² mol) and 40 ml of toluene. Themixture was heated to reflux (about 115° C.), under vigorous stirring,and maintained for 28 hours. The conversion checked by GC was about 44%(after 20 hours the conversion checked by GC was about 43%).

After cooling to 60° C., 50 mL of Toluene and 40 mL of water were addedand the mixture was cooled to 50° C. under stirring. The residualcarbonate were then dissolved by slow addition of aqueous HCl 32% untilsolution reached pH=2-3. The mixture was maintained under stirring at50° C. for ½ hour before the organic layer was separated. The organiclayer was treated several times with saturated solution of SodiumChloride and water under stirring at 50° C. and concentrated, by solventdistillation at reduced pressure. The crude product was obtained as anoil (41 g)

Examples 8-18 illustrate variations of theCuI-Ethylenediamine-K₂CO₃-toluene system. They were performed accordingto the procedure of example 1 except for the details specified. Theamounts are given relative to the amount of 5-chloro-indole (calculatedas pure 5-chloro-indole). % means mol %, equivalent means molarequivalent, and volume means ml of solvent per g of 5-chloro-indole.

Example 8

10% of CuI, 15% of ethylenediamine, 2.1 equivalent of K₂CO₃, 1.1equivalent of 4-fluoro-bromobenzene, 2 volumes of toluene, 16 h reflux.The conversion checked by GC was about 99.5%.

Example 9

1% of CuI, 5% of ethylenediamine, 1.5 equivalent of K₂CO₃, 1.1equivalent of 4-fluoro-bromobenzene, 2 volumes of toluene, 10 h reflux.The conversion checked by GC was about 52%.

Example 10

1% of CuI, 5% of ethylenediamine, 1.5 equivalent of K₂CO₃, 1.3equivalent of 4-fluoro-bromobenzene, 2 volumes of toluene, 10 h reflux.The conversion checked by GC was about 45%.

Example 11

5% of CuI, 15% of ethylenediamine, 1.05 equivalent of K₂CO₃, 1.2equivalent of 4-fluoro-bromobenzene, 2 volumes of toluene, 18 hdistilling off water as azeotrope and recycling toluene. The conversionchecked by GC was about 55%.

Example 12

5% of CuI, 15% of ethylenediamine, 2.1 equivalent of K₂CO₃, 1.1equivalent of 4-fluoro-bromobenzene, 2 volumes of toluene, 36 h reflux.The conversion checked by GC was about 96%.

Example 13

5% of CuI, 15% of ethylenediamine, 1.5 equivalent of K₂CO₃, 1.1equivalent of 4-fluoro-bromobenzene, 2 volumes of toluene, 36 h reflux.The conversion checked by GC was about 95%.

Example 14

5% of CuI, 20% of ethylenediamine, 1.1 equivalent of K₂CO₃, 1.1equivalent of 4-fluoro-bromobenzene, 2 volumes of Toluene, 44 h reflux.The conversion checked by GC was about 99%.

Example 15

5% of CuI, 20% of ethylenediamine, 1.1 equivalent of K₂CO₃, 2 equivalentof 4-fluoro-bromobenzene, 2 volumes of toluene, 36 h reflux. Addition ofCuI in two portions (2×2.5%, 2^(nd) after 10 h refluxing). Theconversion checked by GC was about 98%.

Example 16

5% of CuI, 1.14 equivalent of ethylenediamine, 1.1 equivalent of K₂CO₃,2 equivalent of 4-fluoro-bromobenzene, 2 volumes of toluene, 24 hreflux. The conversion checked by GC was about 86%.

Example 17

2.5% of CuI, 40% of ethylenediamine, 1.1 equivalent of K₂CO₃, 2equivalent of 4-fluoro-bromobenzene, 2 volumes of toluene, 26 h reflux.The conversion checked by GC was about 87%.

Example 18 Under Moderate Pressure

5% of CuI, 20% of ethylenediamine, 1.1 equivalent of K₂CO₃, 2 equivalentof 4-fluoro-bromobenzene, 2 volumes of toluene. The reaction mixture washeated to 120° C. in a closed reactor for 44 h allowing the pressure toincrease to a maximum of 2 bar. The conversion checked by GC was about87%.

Toluene and Water as Solvent System

Example 19 K₃PO₄ as base

A jacketed glass reactor was charged with 40 g of crude 5-chloro-indole(80% pure as determined by HPLC) (32 g, 0.211 mol), K₃PO₄ (56 g, 0.264mol), ⁴-fluoro-bromobenzene (92.3 g, 0.5277 mol), CuI (2.5 g, 1.32*10⁻²mol), ethylenediamine (3.2 g, 5.28*10⁻² mol), 80 mL of toluene and 20 mlof water. The mixture was heated to reflux (about 115° C.), undervigorous stirring, and maintained for 40 hours. The conversion checkedby GC was about 89%.

After cooling to 60° C., 80 mL of Toluene and 80 mL of water were addedand the mixture was maintained under stirring at 50° C. for ½ hour andthe organic layer was separated and treated with 80 mL of water. Theresidual phosphates were then dissolved by slow addition of aqueous HCl32% until solution reached pH=2-3. The mixture was maintained understirring at 50° C. for ½ hour the aqueous layers were eliminated. Theorganic layer was then concentrated, by solvent distillation at reducedpressure, and the crude product was obtained as an oil (86.4 g).

Example 20 K₂CO₃ as base

A jacketed glass reactor was charged with 40 g of crude 5-chloro-indole(80% pure as determined by HPLC) (32 g, 0.211 mol), K₂CO₃ (40.2 g, 0.290mol), 4-fluoro-bromobenzene (92.3 g, 0.5277 mol), CuI (2.5 g, 1.32*10⁻²mol), ethylenediamine (3.2 g, 5.28*10⁻² mol), 80 ml of toluene and 20 mLof water. The mixture was heated to reflux (about 110° C.), undervigorous stirring, and maintained for 36 hours. The conversion checkedby GC was about 67%.

After cooling to 60° C., 80 mL of toluene and 80 mL of water were addedand the mixture was maintained under stirring at 50° C. for ½ hour andthe organic layer were separated and treated with 80 mL of water. Theresidual carbonates were then dissolved by slow addition of aqueous HCl32% until solution reached pH=2-3. The mixture was maintained understirring at 50° C. for ½ hour the aqueous layers were eliminated. Theorganic layer was then concentrated, by solvent distillation at reducedpressure, and the crude product was obtained as an oil (68 g). Theyield, based on HPLC (assay against ext. Std.), was about 50%.

Dimethylformamide (DMF) as a Solvent

Example 21

A glass jacketed reactor was charged, under nitrogen, with distilled5-chloro-indole (94% pure as determined by HPLC) (200 g, 1.32 mol),K₂CO₃ (200 g, 1.45 mol), 4-fluoro-bromobenzene (461 g, 2.63 mol), CuI(12.6 g, 0.066 mol), ethylenediamine (15.9 g, 0.26 mol) and 400 mL ofdimethylformamide. The mixture was heated to 40° C. under vigorousstirring and kept at that temperature for 12 hours whereafter themixture was to reflux (about 130-135° C.), under vigorous stirring, byincreasing the jacket temperature over period of 45 minutes to 145° C.and maintained at reflux for 5 hours.

After cooling to 60° C., 400 mL of toluene and 400 mL of water wereadded and the mixture was cooled to 50° C. under stirring. The organicphase was separated and washed, at 50° C. with diluted hydrochloric acid(5 ml HCl 32%+100 ml H₂O) and finally with a solution of diluted ammonia(5 mL of NH3 33%+200 mL of H₂O). The solvent was then removed bydistillation at reduced pressure and the crude product was obtained asan oil (469 g). The yield, based on HPLC (assay against ext. Std.), wasabout 94%.

Example 22 CuBr as Catalyst Source

A glass jacketed reactor was charged with 20 g of crude 5-chloro-indole(80% pure as determined by HPLC) (16 g, 0.106 mol), K₂CO₃ (20 g, 0.144mol), 4-fluoro-bromobenzene (47.7 g, 0.27 mol), CuBr (0.95 g, 6.6*10⁻³mol), ethylenediamine (1.58 g, 2.6*10⁻² mol) and 40 mL ofdimethylformamide. The mixture was heated to reflux (about 130-135° C.),under vigorous stirring, and maintained for 20 hours. The conversionchecked by GC was about 99.5% (after 6 hours the conversion checked byGC was about 81%).

After cooling to 60° C., 80 mL of Toluene and 40 mL of water were addedand the mixture was cooled to 50° C. under stirring. The residualcarbonate were then dissolved by slow addition of aqueous HCl 32% untilsolution reached pH=2-3. The mixture was maintained under stirring at50° C. for ½ hour. The organic layer was separated and treated with 40mL of water. The mixture was maintained under stirring at 50° C. for ½hour the aqueous layers were eliminated. The organic layer was treatedseveral times with saturated solution of ammonium sulphate and waterunder stirring at 50° C. and then concentrated by solvent distillationat reduced pressure. The crude product was obtained as an oil (38.4 g).The yield, based on HPLC (assay against ext. Std.), was about 80%.

Example 23 CuCl and KI as Catalyst Source

A glass jacketed reactor was charged with 20 g of crude 5-chloro-indole(80% pure as determined by HPLC) (16 g, 0.106 mol), K₂CO₃ (20 g, 0.144mol), 4-fluoro-bromobenzene (47.7 g, 0.27 mol), CuCl (0.595 g, 6.0*10⁻³mol), ethylenediamine (1.58 g, 2.6*10⁻² mol) and 40 mL ofdimethylformamide. The mixture was heated to reflux (about 130-135° C.),under vigorous stirring. After 4 hours was added KI (1.16 g, 6.99*10⁻³mol). The mixture was then maintained at reflux for 16 h. The conversionchecked by GC was about 99.5% (after 6 hours the conversion checked byGC was about 53%).

After cooling to-60° C., 80 mL of Toluene and 40 mL of water were addedand the mixture was cooled to 50° C. under stirring. The residualcarbonates were then dissolved by slow addition of aqueous HCl 32% untilsolution reached pH=2-3. The mixture was maintained under stirring at50° C. for 12 hour the organic layer were separated and treated with 40mL of water. The mixture was maintained under stirring at 50° C. for ½hour the aqueous layers were eliminated. The organic layer was treatedseveral times with saturated solution of ammonium sulfate and waterunder stirring at 50° C. then and concentrated, by solvent distillationat reduced pressure. The crude product was obtained as an oil (37.5 g).The yield, based on HPLC (assay against ext. Std.), was about 82%.

Examples 24-29 illustrate variations of theCuI-Ethylenediamine-K₂CO₃-Dimethylformamide system. They were performedaccording to the procedure of example 21 except for the scale which was40 g of 5-chloro-indole and the details specified. The amounts are givenrelative to the amount of 5-chloro-indole (calculated as pure5-chloro-indole). % means mol %, equivalent means molar equivalent, andvolume means ml of solvent per g of 5-chloro-indole.

Example 24

5% of CuI, 20% of ethylenediamine, 1.1 mol of K₂CO₃, 2 mol of4-fluoro-bromobenzene, 2 volumes of dimethylformamide, 29 h 120° C. Theconversion checked by GC was about 80%.

Example 25

5% of CuI, 20% of ethylenediamine, 1.1 mol of K₂CO₃, 2 mol of4-fluoro-bromobenzene, 2 volumes of dimethylformamide, 6 h 135° C. Theconversion checked by GC was about 99%.

Example 26

5% of Cul, 20% of ethylenediamine, 1.1 mol of K₂CO₃, 1.2 mol of4-fluoro-bromobenzene, 2 volumes of dimethylformamide. Pretreatment ofcatalytic system 1 h at 50° C. Reaction 5.5 h 135° C. The conversionchecked by GC was about 94%.

Example 27

5% of CuI, 20% of ethylenediamine, 1.1 mol of K₂CO₃, 2 mol of4-fluoro-bromobenzene, 2 volumes of dimethylformamide and 0.5 volumes ofwater. Pretreatment of catalytic system 1 h at 50° C. Reaction 19 h 118°C. (reflux). The conversion checked by GC was about 58%.

Example 28

5% of CuI, 20% of ethylenediamine, 1.1 mol of K₂CO₃, 2 mol of4-fluoro-bromobenzene, 2 volumes of Dimethylformamide. Pretreatment ofcatalytic system 14 h at 50° C. Reaction 7 h 135° C. The conversionchecked by GC was about 92.2%.

Example 29

5% of CuI, 20% of ethylenediamine, 1.1 mol of K₂CO₃, 2 mol of4-fluoro-bromobenzene, 2 volumes of dimethylformamide. NO Pretreatmentof catalytic system 50° C. Reaction 7 h 135° C. The conversion checkedby GC was about 78%.

Example 30 illustrates the removal of the impurity5-bromo-1-(4-fluorophenyl)-indole, which is generated in levels up to 1%by performing a halogen exchange during work-up. Lowering of theimpurity by recrystallisation turned out to be difficult.

Example 30

A glass jacketed reactor was charged, under nitrogen, with5-chloroindole (200 g, 1.32 mol), K₂CO₃ (200 g, 1.45 mol),4-bromo-fluorobenzene (347 g, 1.98 mol) and 400 ml of dimethylformamide.The mixture was heated to 50° C. and ethylenediamine (16 g, 0.26 mol)and CuI (12.5 g, 0.066 mol) were charged in the reactor. The mixture waskept at that temperature for 1.5 hours, then was heated up to 130° C.for 1 hour and finally was heated to reflux temperature (about 139° C.)for 4 hours. The conversion checked by HPLC was >95%. When the couplingreaction was completed (ref. Example.doc), the mixture was cooled to100° C. and 800 ml of toluene were added. After cooling to 60° C. themixture was washed with a solution of diluted ammonia (80 ml of NH₃30%+400 ml of H₂O). The organic phase was washed at 40° C. with dilutedhydrochloric acid (50 ml of HCl 32%+200 ml of H₂O) and finally withdiluted ammonia (44 ml of NH330%+300 ml of water). The organic solutionwas concentrated by distillation at normal pressure and then at reducedpressure by stripping with 1-methyl-2-pyrrolidinone (NMP). The residuewas diluted with NMP. CuCl (17-35 g, 0.17-0.35 mol) and CuI (2.5g, 0.013mol) were charged in the reactor and mixture was heated up to 140° C.for 6 hours. After diluting with toluene (600 ml), the mixture wasfiltered and then washed with ammonia (45 ml of NH₃ 30%+300 ml of H₂O).The organic phase was concentrated by distillation at normal pressure,then was diluted with sulfolane and concentrated under vacuum. The crudewas finally purified by thin film distillation.

Dioxane as Solvent

Example 31 Trans-1,2-Cyclohexanediamine as Ligand

A jacketed glass reactor was charged with 5 g of crude 5-chloro-indole(80% pure as determined by HPLC) (4 g, 2.6*10⁻² mol), K₂CO₃ (9.58 g,6.9*10⁻² mol), 4-fluoro-bromobenzene (6.34 g, 3.6*10⁻² mol), CuI(0.063g, 6.6*10⁻⁴ mol), trans-1,2-cyclohexanediamine (0.377 g, 3.3*10⁻³ mol)and 33 mL of dioxane. The mixture was heated to about 110° C., undervigorous stirring, and maintained for 25 hours. The conversion checkedby GC was about 45%.

After cooling to 60° C., the solid residual were filtered off and theorganic solution was then concentrated, by solvent distillation atreduced pressure, and the crude product was obtained as an oil (8.2 g).

Neat—Without Solvent

Example 32

A jacketed glass reactor was charged with 30 g of distilled 5-Cl-indole(96% pure as determined by BPLC) (28.8 g, 0.190 moles), K₂CO₃ (30.1 g,0.218 moles), 4-fluoro-bromobenzene (143.4 g, 0.819 moles), CuI (1.88 g,9.89*10⁻³ moles) and ethylenediamine (2.38 g, 3.96*10⁻² moles). Themixture was heated to 130-135° C. under vigorous stirring, andmaintained for 5 hours.

After cooling to 50° C., 80 mL of Toluene and 80 mL of water were addedand the mixture was maintained under stirring at 50° C. for 15 minutes.The residual carbonates were then dissolved by slow addition of H₂SO₄36% until solution reached pH=2-3 (about 40 mL). The mixture wasmaintained under stirring at 50° C. for ½ hour then cooled to roomtemperature and stirred overnight. The aqueous layer (upper phase) waseliminated. The organic phase was washed two times with water (2×50 mL)and then concentrated, by solvent distillation at reduced pressure. Thecrude product was obtained as an oil (115.9 g). The yield, based on HPLC(assay against ext. Std.), was about 42%.

1. A method for manufacture of sertindole comprising manufacturing5-chloro-1-(4-fluorophenyl)-indole and converting it to sertindolecharacterised in that the method for manufacture of5-chloro-1-(4-fluorophenyl)-indole comprises reacting 5-chloro-indolewith a 4-fluorophenylhalide in the presence of a base, a chelatingligand and catalytic amounts of a copper salt comprising copper(I) orcopper(II) and an anion which does not interfere in an unfavourable waywith the reaction.
 2. A method for manufacture of5-chloro-1-(4-fluorophenyl)-indole comprising reacting 5-chloro-indolewith a 4-fluorophenylhalide in the presence of a base, a chelatingligand and catalytic amounts of a copper salt comprising copper(I) orcopper(II) and an anion which does not interfere in an unfavourable waywith the reaction.
 3. The method according to claim 1 characterised inthat the chelating ligand is a substituted or unsubstituted1,10-phenanthroline or a compound of the formulaX—(CR¹R²—(CR⁵R⁶)_(n)(CR³R⁴—Y)_(m), wherein X and Y independently areselected from NR⁷R⁸ and OR⁹, R¹—R⁹ independently are selected fromhydrogen, C₁₋₆-alkyl, C₁₋₆-alkyl carboxylic acid and aryl or one of R¹and R² together with one of R⁵ and R⁶ are C₃₋₆-alkylene, m is 1 or 2 andn is 0, 1, 2 or
 3. 4. The method according to claim 3 characterised inthat the chelating ligand is selected from 1,2-cyclohexanediamine, N, N,N, N-tetramethyl ethylenediamine, N, N-diethyl ethylenediamine,ethylenediamine, ethylenediamine N, N, N, N-tetraacetic acid (EDTA),diethylenetriamine N, N,N, N, N-pentaacetic acid (DTPA) and substitutedor unsubstituted 1, 10-phenantroline.
 5. The method according to claim 1characterised in that the copper is selected from CuCl, CuBr, CuI,CuCl₂, CuBr₂, CuI₂, CuOCOCH₃, Cu(OCOCH₃)₂, anhydrous or hydrated CuSO₄,CuCO₃, Cu₂O and mixtures of said copper salts.
 6. The method to claim 1characterised in that the 4-fluorophenylhalide is 4-fluoro-bromobenzeneor 4-fluoro-iodobenzene.
 7. The method according to claim 1characterised in that the 4-fluorophenylhalide is added in a molarsurplus relative to the 5-chloro-indole.
 8. The method according toclaim 7 characterised in that the molar surplus is in the range from 1.1to
 3. 9. The method according to claim 1 characterised in that thecatalytic amounts of the copper salt is less than 20 mol % relative tothe 5-chloro-indole.
 10. The method according to claim 1 characterisedin that the base is selected from the carbonates, hydrogen carbonates,phosphates, hydrogen phosphates, dihydrogen phosphates, oxides andhydroxides of alkali metals.
 11. The method according to claim 10characterised in that the base is present in a molar excess relative tothe 5-chloro-indole.
 12. The method according to claim 1 characterisedin that the reaction is completed at temperatures in the range fromabove 80° C. to 200° C.
 13. The method according to claim 4, wherein thechelating ligand is 1,2-cyclohexanediamine, N, N, N, N-tetramethylethylenediamine, N, N-diethyl ethylenediamine or ethylenediamine. 14.The method according to claim 13, wherein the chelating ligand isethylenediamine.
 15. The method according to claim 5, wherein the coppersalt is selected from CuCl, CuBr, CuI, CuCl₂, CuBr₂ and CuI₂.
 16. Themethod according to claim 6, wherein the 4-fluorophenylhalide is4-fluoro-bromobenzene.
 17. The method according to claim 9, wherein thecatalytic amounts of the copper salt is less than 10 mol % relative tothe 5-chloro-indole.
 18. The method according to claim 17, wherein thecatalytic amounts of the copper salt is in the range from about 1 toabout 5 mol % relative to the 5-chloro-indole.
 19. The method accordingto claim 11, wherein the base is present in the range from about 1.05molar equivalents to about 2.5 molar equivalents.
 20. The methodaccording to claim 12, wherein the reaction is completed at temperaturesin the range from 100° C. to 160° C.